We are performing global exon expression profiling to complement the ongoing positional cloning effort to identify susceptibility genes for diabetes and its predictors, insulin resistance, insulin secertory dysfunction and obesity. To this end, we are examining exon expression profiles in tissue samples from non-diabetic full-blooded Pima Indians using Affymetrix exon arrys that query over 1 million known and predicted exons across the entire genome. We have collected 225 skeletal muscle tissue samples and 250 adipose tissue samples from non-diabetic Pima Indians who have been metabolically phenotyped for body composition and insulin action in vivo using the hyperinsulinemic euglycemic clamp. Follow up data is available on the diabtic status of most of these volunteers, up to 7-10 years later, so will be able to identify a prediabtic exon expression profile in this population. We have completed the exon arrays on all skeletal muscle and adipose tissue samples and are currently analyzing these data and comparing to genotypic data collected on many of the subjects from our genome-wide association study using single nucleotide polymorphisms. Initial analyses ahve identified several trancripts with a bimodal distribuiton apparently due to cis acting DNA elements. One of these transcripts was HLA-DRB1 and levels of this trancript were associated with early insulin secretion indicating an autoimmune regulation of insulin secretion in this population.